Workneh et al.

Infectious Diseases of Poverty (2016) 5:22

DOI 10.1186/s40249-016-0115-z

RESEARCH ARTICLE Open Access

Diabetes mellitus is associated with

increased mortality during tuberculosis
treatment: a prospective cohort study
among tuberculosis patients in South-
Eastern Amahra Region, Ethiopia
Mahteme Haile Workneh1,2*, Gunnar Aksel Bjune1 and Solomon Abebe Yimer1,2,3,4

Abstract
Background: There is growing evidence suggesting that diabetes mellitus (DM) affects disease presentation and
treatment outcome in tuberculosis (TB) patients. This study aimed at investigating the role of DM on clinical
presentations and treatment outcomes among newly diagnosed TB patients.
Methods: A prospective cohort study was conducted in South-Eastern Amhara Region, Ethiopia from September
2013 till March 2015. Study subjects were consecutively recruited from 44 randomly selected health facilities in the
study area. Participants were categorized into two patient groups, namely, patients with TB and DM (TBDM) and TB
patients without DM (TBNDM). Findings on clinical presentations and treatment outcomes were compared between
the two patient groups. Cox proportional hazard regression analysis was applied to identify factors associated with
death.
Results: Out of 1314 TB patients enrolled in the study, 109 (8.3 %) had coexisting DM. TBDM comorbidity [adjusted
hazard ratio (AHR) 3.96; 95 % confidence interval (C.I.) (1.76–8.89)], and TB coinfection with human immunodeficiency
virus (HIV) [AHR 2.59; 95 % C.I. (1.21–5.59)] were associated with increased death. TBDM and TBNDM patients did not
show significant difference in clinical symptoms at baseline and during anti-TB treatment period. However, at the 2nd
month of treatment, TBDM patients were more symptomatic compared to patients in the TBNDM group.
Conclusions: The study showed that DM is associated with increased death during TB treatment. DM has no
association with clinical presentation of TB except at the end of the intensive phase treatment. Routine screening
of TB patients for DM is recommended for early diagnosis and treatment of patients with TBDM comorbidity.
Keywords: Tuberculosis, Diabetes mellitus, Association, Symptoms, Treatment outcome, Amhara Region, Ethiopia

Multilingual abstracts Background

Please see Additional file 1 for translations of the abstract
into the six official working languages of the United
Nations.
* Correspondence: maykm24@yahoo.com
1
Institute of Health and Society, Faculty of Medicine, University of Oslo, Oslo,
Norway
2
Amhara Regional State Health Bureau, Bahir-Dar, Ethiopia
Full list of author information is available at the end of the article
Tuberculosis (TB) is a major public health threat in the
developing world [1]. It is clear that the current TB control
strategy has reduced the TB incidence [1, 2]. However,
there are more TB cases today than at any other time in
history [3]. This is because of the emergence of multidrug-
resistant (MDR) TB strains, human immunodeficiency
virus (HIV) epidemic [3] and other risk factors such as
smoking, diabetes mellitus (DM), malnutrition, alcohol
abuse, indoor air pollution, malignancies and an aging
population [4].

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Workneh et al. Infectious Diseases of Poverty (2016) 5:22
DM has recently shown an alarming increase worldwide
and there is growing evidence indicating that DM affects
TB disease presentation and treatment outcome [5, 6]. A
number of studies showed higher frequencies of certain
clinical findings such as lower lung field lesions, cavities
and acid-fast bacilli (AFB) smear positivity among patients
with TB and DM (TBDM) comorbidity [7–10]. Adverse
effects of DM on TB treatment outcomes, i.e. increased
risk of death, treatment failure, default and relapse were
reported in many studies [11, 12]. Few studies reported
small or no difference in clinical presentations and treat-
ment outcomes between TBDM and TB without DM
(TBNDM) patient groups [13, 14].
Sub-Saharan African countries which are the epicenter
for TB and HIV infection are currently affected by the
growing burden of DM. The interaction of these diseases
is conspiring to increase the negative impacts of all three
conditions in sub-Saharan Africa more than any other
region [15]. Ethiopia is one of the high TB burden coun-
tries in sub-Saharan Africa. According to the World
Health Organization (WHO) report, the country has cur-
rently achieved the 2015 Millennium Development Goal
(MDG) targets of reducing cases and deaths from TB [16].
However, the growing challenges of MDR-TB and TB/HIV
coinfection are affecting the TB control efforts [16, 17]. Re-
cent studies in Ethiopia reported that DM is contributing
to increased TB burden. Few studies conducted in the Am-
hara Region of Ethiopia showed high prevalence of DM
among TB patients [18, 19]. Nonetheless, no study to date
has investigated the association of DM with clinical presen-
tations and treatment outcomes of TB in the region. Thus,
this study was conducted to explore the role of DM on
clinical presentations and treatment outcomes of newly di-
agnosed TB patients.
Methods
Study area and setting
The study was conducted in South-Eastern part of
Amhara Region, Ethiopia. South-Eastern Amhara Region
consists of four zones and one City Administration,
namely, North Wollo, South Wollo, North Shewa, Oromia
Special Zone and Dessie City Administration. The total
population is estimated at 7,358,301, and of these were
3,684,735 men and 3,673,566 women [20].
Study design and population
A prospective cohort study was conducted in 44 randomly
selected health facilities (HFs) in the study area. The study
population included all newly diagnosed TB patients aged
15 years and above who were consecutively registered for
treatment at the directly observed treatment short course
(DOTS) units. The study was conducted from September
2013 till March 2015. Study subjects were categorized into
TBDM and TBNDM patient groups. Each patient group
Page 2 of 10
was followed from enrollment until completion of anti-TB
treatment.
Sampling method and sample size
Random sampling technique was applied to select study
sites. There were a total of 420 HFs (326 (78 %) govern-
ment and 94 (22 %) private HFs) in the study area, of
these, only 102 (31 %) government and 20 (21 %) private
HFs were eligible to provide TB, HIV and DM diagnostic
and treatment services. Among the 20 private HFs, only
5 (25 %) provided TB, HIV and DM services in a continu-
ous manner. Fifteen (75 %) of the private HFs encountered
frequent TB service interruption for various reasons and
were excluded from the study. Finally, out of the 102
(31 %) government HFs eligible for the study, 39 (38 %)
HFs were randomly selected. By adding the five private
HFs that were continuously providing TB, HIV and DM
services in the study area, a total of 44 HFs were selected
as study sites.
Sample size was calculated using the standard formula
for estimating single population proportion, (n) = {[z2*p
(1-p)]/d2}. We considered 95 % confidence interval (CI)
and a margin error of 3 %. As there were no previous
similar studies in the study area, we also assumed that
50 % of the TB patients would have difference in clinical
presentations and treatment outcomes. Based on these
assumptions, the minimum sample size required for the
study was estimated at 1067. By adding 10 % for non-
response, the total sample size was calculated to be 1174
patients. However, we included all of the 1335 patients
that reported to the study sites during the study period.
This amounted to 113 % of the minimum sample size
required for the study.
Inclusion and exclusion criteria
Newly diagnosed TB patients aged 15 years and above,
known DM patients who were newly diagnosed for TB,
newly diagnosed TB patients who at the initiation of TB
treatment were negative for DM investigation but de-
veloped DM during the course of ant-TB treatment,
transferred-in TB patients who had never started treat-
ment in the transferring out HFs, and newly diagnosed
TB patients who started and completed their treatment
in the selected study sites and satellite health posts
were included in the study, whereas TB patients less
than 15 years of age, retreatment cases, patients who
could not offer informed consent, known or suspected
MDR-TB cases, patients with malignancy and patients
who were on immunosuppressive therapy were ex-
cluded from the study.
TB diagnosis, disease classification, treatment protocol
and treatment outcome evaluations were defined accord-
ing to the national and WHO guideline [17, 21]. DM
was diagnosed by performing screening tests at least two
Workneh et al. Infectious Diseases of Poverty (2016) 5:22
times by random blood glucose (RBS) and/or fasting
blood glucose (FBS) tests in accordance with the WHO
diagnostic criteria [22]. In addition, self-reporting of DM
was used to document previous history of DM. Ziehl-
Neelsen staining technique was applied for the detection
of AFB by microscopy. All patient groups were treated
based on standardized anti-TB treatment regimen regard-
less of their DM status [17, 21]. Study participants were
prospectively followed for 6 months until treatment out-
comes were evaluated.
Patients’ responses to treatment were assessed by clin-
ical assessment of sign and symptoms, body weight meas-
urement and follow-up of sputum smear examination
results at the end of 2nd, 5thand 6th months of anti-TB
treatment period. If patient’s sputum was positive for AFB
at the end of the 2nd month of treatment, sputum smear
examination was repeated after 1 month. When a patient
remained positive at the end of the 3rd month of treat-
ment, sputum was taken for culture and drug susceptibil-
ity testing. Treatment outcomes were classified as cured,
treatment completed, death, treatment failure and de-
faulter [17, 21]. In this analysis, cure and treatment com-
pleted were categorized as successful treatment outcomes,
whereas death, treatment failure and defaulter were con-
sidered as unsuccessful treatment outcomes. Provider
initiated counseling and testing (PICT) service was pro-
vided to screen patients for HIV.
Operational definitions of variables
Uneducated: study participants who had no formal
schooling.
Educated: study participants who attained formal
schooling.
Good adherence to anti-TB treatment: patients who
took ≥95 % of the prescribed anti-TB regimens.
Good adherence to DM therapy: the extent to which a
DM patient practices health worker’s advices (i.e. advises
about taking medications, diet, physical activity and attend-
ing follow-up visits in DOTS units) which corresponds to
implementing 100 % of the recommendations from a health
care provider.
Data collection and quality control
Health workers who were responsible for TB patient care
at DOTS units, laboratory technologists, and clinicians re-
sponsible for diagnosis, treatment as well as follow-up of
TB and DM patients were trained and assigned as data
collectors at each study site. Socio-demographic and clin-
ical characteristics of participants were collected using
pre-tested semi-structured questionnaire. Clinical and
bacteriological characteristics of participants were docu-
mented at baseline and during follow-up periods. Data
quality was assured by trained supervisors and the principal
investigator who regularly checked for data completeness.
Page 3 of 10
Blood glucose measurement and weight scale were cali-
brated before measuring patient’s blood glucose level
and body weight. AFB results were checked by internal
and external quality control methods.
Ethical approval
Ethical approval was obtained from the Regional Commit-
tee for Research Ethics in Norway (REC-Øst, Norway)
(Reference 2013/829/REK sør-øst dated: 05.06.2013) and
Ethiopian Science and Technology Ministry (Reference
3.10/355106 dated: 08/01/06). Ethical approval was also
secured from health authorities of the study area before
the initiation of the study. Patients were informed about
the nature of the study and written consent was solicited
prior to their participation in the study. Parents/guardians
gave informed consent for patients aged 15 to 17 years.
TB patients who were found to have DM, MDR-TB and
HIV were linked to DM clinics, MDR-TB treatment cen-
ters and anti-retroviral therapy (ART) clinics, respectively
for further investigation and management.
Statistical analysis
Data were entered, cleaned and analyzed using Statistical
Package for Social Science (SPSS) version 22 Armonk,
New York 10504 IBM Corp. software. The original ques-
tionnaire was referred and errors corrected by re-entry
when inconsistencies occurred. Chi-square test and Fish-
er’s exact test were used to compare categorical variables
as appropriate. Student’s t test was applied to compare
means for normally distributed variables. Socio-demographic,
clinical, and bacteriological parameters were compared
between TBDM and TBNDM patient groups. Clinical
improvements in both patient groups were measured
by assessing decrease in the frequency of clinical symp-
toms, increases in body mass index (BMI) and changes
in sputum smear result during treatment follow-up pe-
riods. Kaplan-Meier plot was used to present time to
sputum smear conversion and death. Cox proportional
hazards regression analysis was performed to investigate
factors associated with sputum smear conversion and
death. A p-value of ≤ 0.05 was considered statistically
significant.
Results
Socio-demographic characteristics of participants
A total of 1335 patients consented to participate in the
study. Twenty one patients were excluded from the ana-
lysis because of non-conclusive DM results. One hundred
and nine (8.3 %) patients had coexisting DM. Majority,
642 (53.3 %) TBNDM patients were males and 59 (54.1 %)
TBDM patients were females. The means and standard
deviations (SD) of participants’ age were 35.0 (±15.0) years
for TBNDM and 43.7 (±15.3) years for TBDM patients
(p < 0.001) (Table 1).
Workneh et al. Infectious Diseases of Poverty (2016) 5:22 Page 4 of 10

Table 1 Socio-demographic characteristics of the study Table 2 Clinical profile of study participants, South-Eastern
participants, South-Eastern Amhara Region, Ethiopia, Amhara Region, Ethiopia, September 2013
September 2013 Type of patients
Type of patients (n = 1314) Characteristics All TB n (%) TBNDM n (%) TBDM n (%) P-value
Variables All TB n (%) TBNDM n (%) TBDM n (%) P-value Type of TB (n = 1314)
Sex PTB 770 (58.6) 700 (58.1) 70 (64.2)
Male 692 (52.7) 642 (53.3) 50 (45.9) EPTB 544 (41.4) 505 (41.9) 39 (35.8) 0.21
Female 622 (47.3) 563 (46.7) 59 (54.1) 0.14 Sputum smear status
Age in years at baseline (n = 770)
15–40 928 (70.6) 877 (72.8) 51 (46.8) <0.001 Negative 420 (54.5) 378 (54.0) 42 (60.0)
41–64 285 (21.7) 240 (19.9) 45 (51.3) Positive 350 (45.5) 322 (46.0) 28 (40.0) 0.33
65–89 101 (7.7) 88 (7.3) 13 (11.9) Type of EPTB
(n = 500)
Mean (± SD) 35.74 (±15.2) 35.02 (±15.0) 43.73 (±15.3) <0.001
TB lymphadenitis 250 (50.0) 237 (51.0) 13 (37.1) 0.30*
Marital status
TB spondylitis 39 (7.8) 36 (7.7) 3 (8.6)
Single 395 (30.1) 373 (31.0) 22 (20.2)
TB peritonitis 36 (7.2) 35 (7.5) 1 (2.9)
Married 919 (69.9) 832 (69.0) 87 (79.8) 0.02
TB enteritis 23 (4.6) 20 (4.3) 3 (8.6)
Religion
Bone TB 18 (3.6) 17 (3.6) 1 (2.9)
Christian 548 (11.7) 508 (42.2) 40 (36.7)
TB abscess 18 (3.6) 16 (3.4) 2 (5.7)
Muslim 766 (58.3) 697 (57.8) 69 (63.3) 0.27
Others 116 (23.2) 104 (22.4) 12 (34.3)
Residence
HIV status (n = 1306)
Rural 488 (37.1) 438 (36.3) 50 (45.9)
Negative 1045 (80.0) 958 (80.0) 87 (79.8)
Urban 826 (62.9) 767 (63.7) 59 (54.1) 0.05
Positive 261 (20.0) 239 (20.0) 22 (20.2) 0.96
Education
HIV therapy (n = 261)
Uneducated 618 (47.0) 558 (46.3) 60 (55.0)
ART 155 (59.4) 143 (59.8) 12 (54.5)
Educated 696 (53.0) 647 (53.7) 49 (45.0) 0.08
Pre-ART 106 (40.6) 96 (40.2) 10 (45.5) 0.63
Occupation
TB: tuberculosis, TBNDM: TB without DM, TBDM: TB and DM, EPTB: extra
Unemployed 376 (28.6) 340 (28.2) 36 (33.0) pulmonary TB, PTB: pulmonary TB, HIV: human immuno deficiency virus,
ART: anti-retroviral
Student 112 (8.5) 106 (8.8) 6 (5.5) *Fisher’s exact test
Self-employed 725 (55.2) 672 (55.8) 53 (48.6)
Government 101 (7.7) 87 (7.2) 14 (12.8) 0.07
employed Clinical presentation and sputum smear conversion
Monthly income At baseline, there was a high frequency of cough 79
(USD)a (72.5 %) and weight loss 94 (86.2 %) among patients in
No income 167 (12.7) 156 (12.9) 11 (10.1) the TBDM group compared to 784 (65.1 %) patients
≤ 18.9 506 (38.5) 465 (38.6) 41 (37.6) with cough and 949 (78.8 %) patients with weight loss in
19–37.9 303 (23.1) 277 (23.0) 26 (23.9) the TBNDM group. At the end of 2nd month of anti-TB
treatment, 23 (23.0 %) TBDM patients had cough com-
≥ 38 338 (25.7) 307 (25.5) 31 (28.4) 0.79
pared to 166 (14.0 %) patients with cough in the TBNDM
TB: tuberculosis, TBNDM: TB without DM, TBDM: TB and DM, SD: standared
deviation, USD: United State Dollar group (p = 0.02). At 5th month, 8 (8.6 %) patients in the
a
1USD = 21.1 Ethiopian birr TBDM category had a BMI value of ≥25 kg/m2 compared
to 42 (3.6 %) patients with BMI of ≥25 kg/m2 in the
TBNDM group (p = 0.05). At 6th month treatment
Clinical profile of study subjects period, 9 (9.7 %) patients in the TBDM group had a
Seven hundred (58.1 %) TBNDM and 70 (64.2 %) TBDM BMI of ≥25 kg/m2 compared to 46 (4.0 %) patients with
patients were pulmonary TB (PTB) cases. Three hundred a BMI value of ≥25 kg/m2 in the TBNDM group (p =
twenty two (46.0 %) TBNDM and 28 (40.0 %) TBDM 0.04) (Table 3). Sputum smear conversion was observed
study participants were smear-positive cases. TB lymph- in 262 (82.4 %) TBNDM and 22 (81.5 %) TBDM pa-
adenitis was the most common form of extra pulmonary tients at the end of 2nd month treatment period (Fig. 1)
TB (EPTB) observed in 237 (51.0 %) TBNDM and 13 (Table 4). Good patient adherence to anti-TB treatment
(37.1 %) TBDM patients (Table 2). was associated with good sputum conversion [adjusted
 Workneh et al. Infectious Diseases of Poverty (2016) 5:22
Table 3 Clinical characteristics of study subjects at baseline, 2nd, 5th and 6th months of anti-TB treatment period, September 2013- March 2015
Months of anti-TB therapy
Clinical symptoms Baseline (n = 1314)a 2nd month (n = 1283)a 5th month (n = 1246)a 6th month (n = 1229)a
TBNDMn (%) TBDMn (%) P-value TBNDMn (%) TBDMn (%) P-value TBNDMn (%) TBDMn (%) P-value TBNDMn (%) TBDMn (%) P-value
Cough 784 (65.1) 79 (72.5) 0.12 166 (14.0) 23 (23.0) 0.02 24 (2.1) 2 (2.2) 1.00* 18 (1.6) 2 (2.2) 0.66*
Fever 933 (78.4) 80 (73.4) 0.34 166 (14.0) 18 (18.0) 0.28 29 (2.5) 2 (2.2) 1.00* 13 (1.1) 1 (1.1) 1.00*
Hemoptysis 228 (18.9) 24 (22.0) 0.43 18 (1.5) 6 (6.0) 0.008 4 (0.3) - - 1 (0.1) - -
Weight loss 949 (78.8) 94 (86.2) 0.06 86 (7.3) 14 (14.0) 0.02 14 (1.2) 2 (2.2) 0.34* 10 (0.9) 1 (1.1) 0.58*
Poor appetite 922 (76.5) 86 (78.9) 0.57 154 (13.0) 16 (16.0) 0.39 25 (2.2) 2 (2.2) 1.00* 10 (0.9) - -
Night sweat 818 (67.9) 75 (68.8) 0.84 121 (10.2) 6 (6.0) 0.17 21 (1.8) 2 (2.2) 0.69* 14 (1.2) 2 (2.2) 0.34*
Dyspnea 587 (48.7) 52 (47.7) 0.84 93 (7.9) 9 (9.0) 0.68 24 (2.1) 2 (2.2) 1.00* 9 (0.8) 2 (2.2) 0.20*
Chest pain 683 (56.7) 64 (58.7) 0.68 108 (9.1) 9 (9.0) 0.96 26 (2.3) 4 (4.3) 0.27* 9 (0.8) 2 (2.2) 0.20*
Fatigue 967 (80.2) 90 (82.6) 0.56 207 (17.5) 29 (29.0) 0.004 46 (4.0) 5 (5.4) 0.42* 21 (1.8) 3 (3.2) 0.42*
BMI (kg/m2)
<18.5 720 (69.5) 59 (54.1) 567 (47.9) 48 (48.0) 424 (36.8) 37 (39.8) 377 (33.2) 33 (35.5)
18.5–24.9 445 (36.9) 44 (40.4) 583 (49.3) 42 (42.0) 686 (59.5) 48 (51.6) 713 (62.8) 51 (54.8)
≥25 31 (2.6) 6 (5.5) 0.13* 33 (2.8) 10 (10.0) 0.002* 42 (3.6) 8 (8.6) 0.05* 46 (4.0) 9 (9.7) 0.04*
Mean (± SD) 18.05 (±2.94) 18.35(±3.72) 0.31 18.95 (±5.79) 21.29 (±20.46) 0.005 19.55 (±3.50) 19.98 (±3.86) 0.26* 19.78 (±2.87) 20.58 (±4.95) 0.02
2
TB: tuberculosis, TBNDM: TB without DM, TBDM: TB and DM, BMI: body mass index, kg: kilogram, m : meter square, SD: standared deviation
*Fisher’s exact test
a
the number of total patients

Page 5 of 10
Workneh et al. Infectious Diseases of Poverty (2016) 5:22 Page 6 of 10

Table 5 Factors associated with sputum smear conversion,

September 2013-March 2015
Characteristics Crude HR P-value Adjusted HR P-value
(95 % C.I.) (95 % C.I.)
Sex
Male
Female 0.98 (0.79–1.22) 0.88 0.99 (0.78–1.24) 0.96
Age in years
15–50
51–89 0.98 (0.67–1.44) 0.93 0.93 (0.63–1.38) 0.72
Residence
Rural
Urban 1.04 (0.82–1.31) 0.76 1.01 (0.79–1.28) 0.95
Type of patient
Fig. 1 Kaplan-Meier curves for sputum smear conversion comparing TBNDM
TBDM Vs. TBNDM patient groups TBDM 0.95 (0.63–1.41) 0.78 0.97 (0.64–1.47) 0.90
HIV status
Negative
hazard ratio (AHR) 3.13; 95 % confidence interval (C.I.),
Positive 1.02 (0.78–1.34) 0.89 1.03 (0.78–1.35) 0.86
(1.34–7.32)] (Table 5).
BMI baseline
(kg/m2)
Treatment outcome
< 18.5
At the end of 6th months anti-TB treatment period, 1135
(94.2 %) TBNDM and 93 (85.3 %) TBDM patients had 18.5–24.9 0.98 (0.77–1.24) 0.86 0.94 (0.73–1.21) 0.62
successful treatment outcomes. The proportion of death ≥ 25 0.98 (0.46–2.08) 0.96 0.99 (0.46–2.13) 0.97
15 (13.8 %) observed in the TBDM patient group was Adherence to TB
higher compared to 42 (3.5 %) deaths seen in the TBNDM Poor
patient category (p < 0.001) (Fig. 2). Only one case of fail- Good 2.92 (1.30–6.55) 0.009 3.13 (1.34-7.32) 0.009
ure to treatment was observed in the TBDM group. A
HR: hazard ratio, C.I.: confidence interval, TBNDM: TB without DM, TBDM: TB and
total of 1187 (98.5 %) patients in the TBNDM and 109 DM, HIV: human immuno deficiency virus, BMI: body mass index, kg: kilogram,
(100 %) participants in the TBDM patient group had good m2: meter square

Table 4 Sputum smear status of study participants at 2nd, 3rd,

5th and 6th months of anti-TB treatment period in South- Eastern
Amhara Region, Ethiopia, September 2013-March 2015
Type of patients
Sputum smear status All TB n (%) TBNDM n (%) TBDM n (%) P-value
2nd month (n = 345)
Positive 61 (17.7) 56 (17.6) 5 (18.5)
Negative 284 (82.3) 262 (82.4) 22 (81.5) 1.00*
rd
3 month (n = 63)
Positive 22 (34.9) 19 (32.8) 3 (60.0)
Negative 41 (65.1) 39 (67.2) 2 (40.0) 0.33*
5th month (n = 324)
Positive 9 (2.8) 9 (3.0) -
Negative 316 (97.2) 290 (97.0) 26 (100.0) 1.00*
th
6 month (n = 318)
Positive 1 (0.3) 1 (0.3) -
Negative 317 (99.7) 291 (99.7) 26 (100.0) 1.00*
Fig. 2 Kaplan-Meier curves for death comparing TBDM Vs. TBNDM
TB: tuberculosis, TBNDM: TB without DM, TBDM: TB and DM patient groups
*Fisher’s exact test
Workneh et al. Infectious Diseases of Poverty (2016) 5:22 Page 7 of 10

adherence to anti-TB treatment. Majority, 64 (58.7 %) of Table 7 Factors associated with death among TB patients in
the TBDM patients had poor adherence to DM therapy South–Eastern Amhara Region, Ethiopia
(Table 6). In multivariate analysis, TBDM comorbidity Variables Crude HR P-value Adjusted HR P-value
[AHR 3.96; 95 % C.I., 1.76–8.89] and TBHIV coinfection (95 % C.I.) (95 % C.I.)
[AHR 2.59; 95 % C.I., 1.21–5.59] were associated with in- Age in years
creased death among patients (Table 7). 15–50
51–89 3.09 (1.80–5.29) <0.001 2.40 (0.99–5.87) 0.05
Type of patient
Discussion
TBNDM
In this study, we found no significant difference in clin-
ical manifestations between TBDM and TBNDM patient TBDM 4.19 (2.33-7.57) <0.001 3.96 (1.76–8.89) 0.001
groups except at the 2nd month of treatment where pa- Education
tients in the TBDM group were more symptomatic Uneducated
compared to their counterparts. The overall successful Educated 0.64 (0.38–1.09) 0.10 0.97 (0.42–2.23) 0.94
treatment outcomes observed in both patient groups Sputum smear
were good and exceeded the WHO target of achieving at baseline
85 % treatment success rate [23]. This may demonstrate Negative
an effective TB control program performance in the study
Positive 0.46 (0.20–1.03) 0.06 0.57 (0.25–1.31) 0.18
area. It may also be an indication of active commit-
HIV status
ment of patients to their TB treatment. In addition,
the result shows that the standard TB treatment regi- Negative
men can be used for managing patients with TBDM co- Positive 2.38 (1.39-4.08) 0.002 2.59 (1.21–5.59) 0.01
morbidity [13, 14]. HR: hazard ratio, C.I.: confidence interval, TB: tuberculosis, TBNDM: TB without
DM, TBDM: TB and DM, HIV: human immuno deficiency virus

There was a significant difference in treatment outcome

Table 6 TB treatment outcome of study participants,
September 2013-March 2015 between TBDM and TBNDM patient groups. Patients in
the TBDM group were four times more likely to die com-
Characteristics All TB TBNDM TBDM P-value
n (%) n (%) n (%) pared to patients in the TBNDM category. This may be
Treatment outcome associated with poor glycemic control and impaired cell
mediated immunity in TBDM patients [24–27]. The find-
Curea 317 (24.1) 291 (24.1) 26 (23.9) 0.95
ing is in line with results of previous studies reported from
Treatment 911 (69.3) 844 (70.0) 67 (61.5) 0.06
completeda
Portugal [9], Maryland [11], Taiwan [24] and Malaysia
[28]. On the other hand, studies conducted in Thailand
Deatha 57 (4.3) 42 (3.5) 15 (13.8) <0.001
and Fiji indicated that the rate of death was similar in both
Treatment failurea 15 (1.1) 14 (1.2) 1 (0.9) 1.00* TBDM and TBNDM patient groups [14, 29]. The unto-
a
Defaulter 14 (1.1) 14 (1.2) - - ward effect of DM may have serious implications in meet-
Total 1314 (100.0) 1205 (91.7) 109 (8.3) ing the 2035 target of achieving 95 % reduction in TB
Over all treatment mortality as set by WHO [30]. Hence, our finding suggests
outcome (n = 1314) a need for DM screening in TB patients. Screening TB pa-
Successful 1228 (93.5) 1135 (94.2) 93 (85.3) tients for DM expedites early detection and treatment of
Unsuccessful 86 (6.5) 70 (5.8) 16 (14.7) <0.001 patients with TBDM comorbidity. It may also enhance op-
timal glycemic control as part of the TBDM patient man-
Adherence to
TB treatment agement [11, 14, 31, 32].
Poor 18 (1.4) 18 (1.5) -
TB/HIV coinfected patients were more likely to die com-
pared to HIV negative TB patients. HIV infection is a
Good 1296 (98.6) 1187 (98.5) 109 (100.0) 0.39
known risk factor for poor TB treatment outcome [33].
Adherence to This finding suggests that there is a need to strengthen
DM therapy
the existing TB/HIV collaborative activities in the study
Poor 64 (58.7) - 64 (58.7) -
area.
Good 45 (51.3) - 45 (51.3) At base line, TBDM and TBNDM patient groups did
TB: tuberculosis, TBNDM: TB without DM, TBDM: TB and DM, DM: not show significant difference in clinical symptoms. The
diabetes mellitus
*Fisher’s exact test
result is in agreement with the findings of several other
a
Each outcome is compared to other treatment outcome category studies done in Saudi Arabia [13], Thailand [14], Turkey
Workneh et al. Infectious Diseases of Poverty (2016) 5:22
[34], Tehran–Iran [35] and Tanzania [36], but is in con-
trast to the studies conducted in Texas-Mexico, Indonesia
and Taiwan where TBDM patients at baseline were more
symptomatic than their counterparts [7, 24, 32]. The rea-
son for insignificant differences in the observed symptoms
between the two patient groups in our study might be re-
lated to early health seeking and start of treatment among
patients.
Weight loss, poor appetite and fatigue were the most
frequent clinical manifestations seen at baseline in TBDM
patients. This may indicate that symptoms of one disease
resembles the other [1, 10, 25], and suggests the need
for a high index of suspicion for TB and DM using bi-
bidirectional screening approach for both diseases [31].
A high proportion of patients in the TBDM and
TBNDM patient groups at baseline had a BMI value of
<18.5 kg/m2. Evidence shows that there is a bidirectional
causal link between undernutrition and active TB. Un-
dernutrition in TB patient’s results in severe illness [37].
Undernutrition may also be a manifestation of poor gly-
cemic control in diabetic TB patients [26]. Malnutrition
stimulates the production of stress hormone which
causes increased blood glucose level in TBDM patients
[9]. Therefore, nutritional support and proper counseling
is essential for patients with TBDM comorbidity [37].
During the course of anti-TB treatment, there was a
significant increase in BMI among patients in the TBDM
group compared to patients in the TBNDM category.
This finding may be related to good recovery of TB ill-
ness among TBDM patients and signals the importance
of adjusting drug dose based on patient’s weight [21].
Participants in the TBDM category were more symptom-
atic at the end of the intensive phase treatment period
compared to patients in the TBNDM group. This finding
is different from a previous observation, where symptom-
atic improvements were seen in both groups of patients at
the 2nd month of anti-TB treatment period [32]. The re-
sult may indicate delay in treatment response in TBDM
patients and this in turn may be linked to poor glycemic
control and lower concentrations of anti-TB drugs in
plasma [24, 25, 38]. Close monitoring of blood glucose
and clinical conditions of TBDM patients during the
treatment period is crucial.
Both TBDM and TBNDM patient groups had better
clinical improvements at 5th and 6th months of anti-TB
chemotherapy compared to the baseline and 2nd month of
treatment. A similar finding was reported from Indonesia
[32]. The result may indicate the effectiveness of the current
anti-TB treatment regimen to manage patients with TBDM
comorbidity.
Sputum smear conversions at the end of 2nd, 5th and
th
6 months of anti-TB treatment period were higher in
both TBDM and TBNDM patient groups. The sputum
conversion result at 2nd month is consistent with the
Page 8 of 10
studies done in Maryland [11], Thailand [14] and Fiji [29],
but is different from the findings of studies conducted
in Texas-Mexico [7], Taiwan [8], Maharashtra-India [10],
Saudi Arabia [13], Taiwan [24] and Turkey [34] where
sputum conversion among TBDM patient groups were
lower. The good sputum smear conversions observed in
both patient groups in our study may be related to good
treatment adherence among patients. Poor adherence to
anti-TB treatment is associated with sub-therapeutic levels
of anti-TB drugs and often results in treatment failure.
In addition, poor adherence to treatment is a driving
force for the emergence and spread of drug-resistant
TB [39, 40].
In this study, no defaulter and only one treatment fail-
ure case was observed in the TBDM patient group com-
pared to a relatively higher number of defaulters and
treatment failure cases observed in TBNDM patient cat-
egory. Studies conducted in Taiwan, Maryland, Thailand
and Indonesia [8, 11, 14, 32] showed that the risk of treat-
ment failure was higher in TBDM patients than patients
in the TBNDM category. The absence of defaulters in the
TBDM patient group is different from the study done in
Thailand [14]. High default rate is a challenge for success-
ful TB control program performance. It is associated with
poor access to HFs, adverse drug reactions, social stigma
and lack of awareness about the consequences of TB
disease [41]. Several reasons including the effective TB
control program implementation in the study area, and
good treatment adherence among patients may have
contributed to the low number of treatment failure and
defaulter cases observed in both patient groups.
This study has several strengths. To the best of our
knowledge, this is one of the very few studies conducted
in Africa and may be used as a baseline for future larger
studies. The study was conducted at all levels of govern-
ment and private HFs. A large number of study partici-
pants selected from urban and rural areas were enrolled
in the study. All these minimize selection bias. In addition,
the study employed cohort study design. Patients were pro-
spectively followed, clinical characteristics and treatment
outcomes were properly documented and findings were
compared in both TBDM and TBNDM patient groups.
Moreover, information bias due to patient transfer out
and lost to follow-up were very well controlled by setting
proper inclusion criteria and conducting strict patient
follow-up during the entire treatment period.
The study has potential limitations. Due to lack of
advanced laboratory facilities for performing all of the
necessary laboratory investigations for screening and
patient follow-up, comparison of findings between
TBDM and TBNDM patient groups were based on rou-
tine biochemical and microscopic test results. There was
poor blood glucose level follow-up in TBDM patients.
Hence, it was not possible to assess the role of blood
Workneh et al. Infectious Diseases of Poverty (2016) 5:22
glucose level on clinical manifestations and mortality
among patients with TBDM comorbidity.
Conclusion
The study showed that DM is associated with increased
mortality during TB treatment. The result also demon-
strated that there is no difference in clinical presenta-
tions and bacteriological findings in both TBDM and
TBNDM patient groups at baseline and during anti-TB
treatment follow-up period. However, at the 2nd month of
treatment, TBDM patients were more symptomatic
compared to patients in the TBNDM group. In order to
expedite early diagnosis and treatment of patients with
TBDM comorbidity, we recommend routine screening
of DM in TB patients in the study area.
Data availability
The data are presented in the main paper and additional
supporting file (Additional file 2).
Additional files
Additional file 1: Multilingual abstracts in the six official working
languages of the United Nations. (PDF 297 kb)
Additional file 2: Dataset used for the manuscript. (XLS 3953 kb)
Abbreviations
AFB: acid fast bacilli; AHR: adjusted hazard ratio; ART: anti-retroviral therapy;
BMI: body mass index; C.I.: confidence interval; DM: diabetes mellitus;
DOTS: directly observed treatment short course; EPTB: extra pulmonary
tuberculosis; FBS: fasting blood sugar; HFs: health facilities; HIV: human
immune-deficiency virus; MDG: Millennium Development Goal;
MDR: multi-drug resistant; PICT: provider initiated counseling and testing;
PTB: pulmonary tuberculosis; RBS: random blood sugar; SD: standard
deviation; SPSS: statistical package for social science; TB: tuberculosis;
TBDM: tuberculosis and diabetes mellitus; TB/HIV: tuberculosis and human
immune-deficiency virus; TBNDM: tuberculosis without diabetes mellitus;
WHO: World Health Organization; USD: United State Dollar.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
MHW, GAB, and SAY: designed the research, MHW: collected the data, MHW,
GAB, and SAY: analyzed the data, MHW: drafted the manuscript. All authors
edited and approved the final manuscript.
Acknowledgments
We would like to acknowledge and thank all levels of health authorities in
the study sites of Amhara Region, Ethiopia for their unreserved support
during data collection period. We are very much grateful to study subjects
for consenting to participate in the study. We are most grateful to all data
collectors who assisted with data collection. Last but not least, we would like
to thank the University of Oslo for providing financial support for the study.
Author details
1
Institute of Health and Society, Faculty of Medicine, University of Oslo, Oslo,
Norway. 2Amhara Regional State Health Bureau, Bahir-Dar, Ethiopia.
3
Department of Microbiology, Oslo University Hospital, Oslo, Norway.
4
Department of Bacteriology and Immunology, Norwegian Institute of Public
Health, Oslo, Norway.
Page 9 of 10
Received: 3 November 2015 Accepted: 14 March 2016
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